Advances in the treatment of childhood cancers have resulted in markedly improved survival rates for many patients. These advancements in therapy, however, have led to new problems, namely, long-term consequences of effective tretments such as the premature loss of gonadal function. Premature ovarian failure (POF) places women at great risk for osteoporosis. The issues raised in this research project, however, differ from usual considerations of age-related menopausal ovarian failure and the accelerated bone loss that ensues. This more typical clinical event follows well after the establishment of peak bone mass. The young women to be investigated in this research project have become estrogen deficient before achieving peak bone mass in this setting. The skeletal profile of young women cancer survivors with ovarian failure will be characterized first. Other potential contributing factors, such as androgen deficiency, growth hormone deficiency, chemotherapeutic agents, nutritional, and other metabolic parameters will be evaluated. The dosage of estrogen required to establish peak bone mass optimally will then be determined. In this prospective, longitudinal study, young cancer survivors with POF will be randomized to one of two estrogen replacement regimens (high dose versus conventional dose). Patients will be monitored every three months for 2 years. Evaluations will include peripheral and central measurements of bone density, indices of bone turnover, and endocrine studies. We anticipate that these studies will yield new information regarding the sufficiency of estrogen replacement therapy in establishing peak bone density in young amenorrheic women. My goal is to become an independent investigator in the field of metabolic bone disease. This award will enable me to obtain new skills in clinical research methods, as well as a greater understanding of the relationship between estrogen and bone modeling in young women. The proposal is particularly fitting for a research career award because it sets the groundwork for future studies, which are essential to my development as an independent investigator. My environment is ideally suited for achieving my goals. My sponsor, Dr. Bilezikian, is an internationally recognized investigator in the field of metabolic bone disease and is committed to providing me with the support I need to pursue my research plans as I make my transition to independent investigator. Through my collaboration with Dr. Sklar, I have access to a large number of young female cancer survivors with ovarian failure. Our Metabolic Bone Unit, with its distinguished tradition in metabolic bone research and education, is an excellent environment in which to develop my career as a clinical investigator.